Abstract
Neurofibromatosis type 2 is a genetic disorder that results in the formation and progressive growth of schwannomas, ependymomas, and/or meningiomas. The NF2 gene encodes the Merlin protein, which links cell cortical elements to the actin cytoskeleton and regulates a number of key enzymes including Group I p21-activated kinases (PAKs), the Hippo-pathway kinase LATS, and mTORC. While PAK1 and PAK2 directly bind Merlin and transmit proliferation and survival signals when Merlin is mutated or absent, inhibition of Group 1 PAKs alone has not proven sufficient to completely stop the growth of NF2-deficient meningiomas or schwannomas in vivo, suggesting the need for a second pathway inhibitor. As the Hippo pathway is also activated in NF2-deficient cells, several inhibitors of the Hippo pathway have recently been developed in the form of YAP-TEAD binding inhibitors. These inhibitors prevent activation of pro-proliferation and anti-apoptotic Hippo pathway effectors. In this study, we show that PAK inhibition slows cell proliferation while TEAD inhibition promotes apoptotic cell death. Finally, we demonstrate the efficacy of PAK and TEAD inhibitor combinations in several NF2-deficient Schwannoma cell lines.
Copyright: © 2024 Benton et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Apoptosis / drug effects
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Cell Line, Tumor
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Cell Proliferation* / drug effects
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Drug Synergism
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Hippo Signaling Pathway*
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Humans
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Neurilemmoma* / genetics
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Neurilemmoma* / metabolism
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Neurilemmoma* / pathology
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Neurofibromatosis 2 / genetics
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Neurofibromatosis 2 / metabolism
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Neurofibromin 2* / deficiency
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Neurofibromin 2* / genetics
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Neurofibromin 2* / metabolism
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Protein Kinase Inhibitors / pharmacology
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Protein Serine-Threonine Kinases* / antagonists & inhibitors
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Protein Serine-Threonine Kinases* / genetics
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Protein Serine-Threonine Kinases* / metabolism
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Signal Transduction* / drug effects
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Transcription Factors* / genetics
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Transcription Factors* / metabolism
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YAP-Signaling Proteins / genetics
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YAP-Signaling Proteins / metabolism
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p21-Activated Kinases* / antagonists & inhibitors
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p21-Activated Kinases* / genetics
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p21-Activated Kinases* / metabolism
Substances
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p21-Activated Kinases
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Neurofibromin 2
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Protein Serine-Threonine Kinases
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Transcription Factors
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NF2 protein, human
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YAP-Signaling Proteins
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Protein Kinase Inhibitors
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Adaptor Proteins, Signal Transducing
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DNA-Binding Proteins
Grants and funding
This work was supported by Children’s Tumor Foundation grant 2121-05-001 to JC and by Ikena Oncology to JC. Children's Tumor Foundation approved study design, but had no role in data collection and analysis, decision to publish, or preparation of the manuscript. Ikena Oncology had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.